{PDOC00929} {PS01209; LDLRA_1} {PS50068; LDLRA_2} {BEGIN} ************************************************************* * LDL-receptor class A (LDLRA) domain signature and profile * ************************************************************* Low-density lipoprotein (LDL) receptors are the major cholesterol-carrying lipoproteins of plasma. Seven successive cysteine-rich repeats of about 40 amino acids are present in the N-terminal of this multidomain membrane protein [1]. Similar domains have been found (see references in [2]) in other extracellular and membrane proteins which are listed below: - Vertebrate very low density lipoprotein (VLDL) receptor, which binds and transports VLDL. Its extracellular domain is composed of 8 LDLRA domains, 3 EGF-like domains and 6 LDL-receptor class B domains (LDLRB). - Vertebrate low-density lipoprotein receptor-related protein 1 (LRP1) (reviewed in [3]), which may act as a receptor for the endocytosis of extracellular ligands. LRP1 contains 31 LDLRA domains and 22 EGF-like domains. - Vertebrate low-density lipoprotein receptor-related protein 2 (LRP2) (also known as gp330 or megalin). LRP2 contains 36 LDLRA domains and 17 EGF-like domains. - A LRP-homolog from Caenorhabditis elegans, which contains 35 LDLRA domains and 17 EGF-like domains. - Drosophila putative vitellogenin receptor, with 13 copies of LDLRA domains and 17 EGF-like repeats. - Complement factor I, which is responsible for cleaving the alpha-chains of C4b and C3b. It consists of a FIMAC domain (Factor I/MAC proteins C6/C7), a scavenger receptor-like domain, 2 copies of LDLRA and a C-terminal serine protease domain. - Complement components C6, C7, C8 and C9. They contain each one LDLRA domain. - Perlecan, a large multidomain basement membrane heparan sulfate proteoglycan composed of 4 LDLRA domains, 3 LamB domains, 12 laminin EGF- like domains, 14-21 IG-like domains, 3 LamG domains, and 4 EGF-like domains. A similar but shorter proteoglycan (UNC52) is found in Caenorhabditis elegans which has 3 repeats of LDLRA. - Invertebrate giant extracellular hemoglobin linker chains, which allow heme-containing chains to construct giant hemoglobin (1 LDLRA domain). - G-protein coupled receptor Grl101 of the snail Lymnaea stagnalis, which might directly transduce signals carried by large extracellular proteins. - Vertebrate enterokinase (EC 3.4.21.9), a type II membrane protein of the intestinal brush border, which activates trypsinogen. It consists at least of a catalytic light chain and a multidomain heavy chain which has 2 LDLRA, a MAM domain (see ), a SRCR domain (see ) and a CUB domain (see ). - Human autosomal dominant polycystic kidney disease protein 1 (PKD1), which is involved in adhesive protein-protein and protein-carbohydrate interactions. The potential calcium-binding site of its single LDLRA domain is missing. - Vertebrate integral membrane protein DGCR2/IDD, a potential adhesion receptor with 1 LDLRA domain, a C-type lectin and a VWFC domain (see ). - Drosophila serine protease nudel (EC 3.4.21.-), which is involved in the induction of dorsoventral polarity of the embryo. It has 11 LDLRA domains, 3 of which miss the first disulfide bond (C1-C3). - Avian subgroup A rous sarcoma virus receptor (1 copy of LDLRA). - Bovine Sco-spondin, which is secreted by the subcommissural organ in embryos and is involved in the modulation of neuronal aggregation. It contains at least 2 EGF-like domains and 3 LDLRA domains. The LDL-receptor class A domain contains 6 disulfide-bound cysteines [4] and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module [2]. A schematic representation of this domain is shown here: +---------------------+ +--------------------------------+ | | | | -CxxxxxxxxxxxxCxxxxxxxxCxxxxxxxxCxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxC- | ******************************************* | | +----------------------------+ 'C': conserved cysteine involved in a disulfide bond. 'x': any residue. '*': position of the pattern. In LDL-receptors the class A domains form the binding site for LDL [1] and calcium [5]. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands [6]. The repeat has been shown [2] to consist of a beta-hairpin structure followed by a series of beta turns. The binding of calcium seems to induce no significant conformational change. -Consensus pattern: C-[VILMA]-x(5,6)-C-[DNH]-x(3)-[DENQHT]-C-x(3,4)-[STADEW]- [DEH]-[DE]-x(1,5)-C [The 4 C's are involved in disulfide bonds] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: 1. -Last update: April 2006 / Pattern revised. [ 1] Yamamoto T., Davis C.G., Brown M.S., Schneider W.J., Casey M.L., Goldstein J.L., Russell D.W. "The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA." Cell 39:27-38(1984). PubMed=6091915 [ 2] Daly N.L., Scanlon M.J., Djordjevic J.T., Kroon P.A., Smith R. "Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor." Proc. Natl. Acad. Sci. U.S.A. 92:6334-6338(1995). PubMed=7603991 [ 3] Krieger M., Herz J. "Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP)." Annu. Rev. Biochem. 63:601-637(1994). PubMed=7979249; DOI=10.1146/annurev.bi.63.070194.003125 [ 4] Bieri S., Djordjevic J.T., Daly N.L., Smith R., Kroon P.A. "Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain." Biochemistry 34:13059-13065(1995). PubMed=7548065 [ 5] van Driel I.R., Goldstein J.L., Suedhof T.C., Brown M.S. J. Biol. Chem. 262:17443-17449(1987). [ 6] Mahley R.W. "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology." Science 240:622-630(1988). 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